Synthetic compounds for treatment of inflammation

ABSTRACT

Novel uses of biologically active bis-heterocyclic e.g. bis-indole alkaloid compounds which have improved activity are disclosed. Pharmaceutical compositions containing the compounds are also disclosed. Specifically, the novel utility pertains to the anti-immunogenic and neurogenic inflammatory properties exhibited by the bis-indole compounds and their analogs.

CROSS-REFERENCE TO A RELATED APPLICATION

[0001] This application is a continuation of U.S. Ser. No. 09/349,316,filed Jul. 8, 1999; which claims priority from provisional applicationU.S. Serial No. 60/091,991, filed Jul. 8, 1998.

[0002] The subject invention was made with government support under aresearch project supported by NOAA Grant No. NA36RG0537. The governmenthas certain rights in this invention.

FIELD OF THE INVENTION

[0003] The subject invention pertains to compounds which are useful asanti-inflammatory agents and to compositions containing such compoundsas active ingredients. More particularly, the invention concerns noveluses for biologically active bis-heterocyclic compounds, e.g.bis-indoles, and to pharmaceutical compositions containing thesecompounds. The novel use of the compounds relates to theanti-inflammatory properties of the disclosed bis-heterocycliccompounds. Specifically exemplified herein are the compounds identifiedas soritin A, HB-238, Bis(3,3′indolyl)methane, HB-236,2-Bis(3,3′indolyl) acetaldehyde, HB-237, and their salts, analogs andderivatives.

[0004] BACKGROUND OF THE INVENTION

[0005] The prevention and control of inflammation is of prime importanceto man, and much research has been devoted to development of compoundshaving anti-inflammatory properties. Certain methods and chemicalcompositions have been developed which aid in inhibiting or controllinginflammation, but additional anti-inflammatory methods and compositionsare needed.

[0006] Bis-heterocyclic compounds such as bis-indoles have beenpreviously described as having antimicrobial, antitumor or antiviralactivity. Specifically, the bis-indole compounds known as topsentins aredisclosed in U.S. Pat. No. 4,866,084. Dragmacidin and its relatedcompounds isolated from the marine sponge of the Dragmacidon sp. aredisclosed in U.S. Pat. No. 4,970,226. These patents are hereinincorporated by reference. These compounds as well as the homocarbonyltopsentins and hamacanthins have also been described as havinginhibitory activity against cellular inflammatory responses. See U.S.Pat. Nos 5,290,777 and 5,464,835 which are also hereby incorporated byreference. The present invention provides compounds having advantageouspotent anti-inflammatory activity.

[0007] Other advantages and further scope of applicability of thepresent invention will become apparent from the detailed descriptionsgiven herein; it should be understood, however that the detaileddescriptions, while indicating preferred embodiments of the invention,are given by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent from such descriptions.

BRIEF SUMMARY OF THE INVENTION

[0008] The present invention provides compounds which are useful asanti-inflammatory agents. The objects of the present invention areaccomplished by the provision of a novel utility for certainbis-heterocyclic compounds.

[0009] In one example, the compounds useful according to the subjectinvention have the following formula:

[0010] R₁₋₁₀ are the same or different selected from —H, —OH, halogen,—COOH, —COOR, C1-C8 alkyl , C1-C8 alkoxyl, mesyl, tosyl, —OCOR, or NZ₁Z₂(wherein the Zs can be the same or different);

[0011] X₁ and X₂ are the same or different selected from —H, —R, —COY,C(NZ₁)Y

[0012] Y is —H, —OH, NZ₁Z₂ (wherein the Z₁ and Z₂ can be the same ordifferent) C1-C8 alkyl, C1- C8 alkoxyl or an amino acid linked throughthe amine functionality forming an amide bond;

[0013] Z₁ and Z₂ are the same or different and independently selectedfrom —H, —OH, C1-C8 alkyl, C1-C8 alkoxyl or —COR;

[0014] R is C1-C8 alkyl, or aryl

[0015] A preferred embodiment of the subject invention pertains to thebis-indole compounds soritin A, HB-238, (I), Bis(3,3′indolyl)methane,HB-236, (II) and 2,2-Bis(3,3′indolyl) acetaldehyde, HB-237 (III).

[0016] As described herein, the invention also comprises pharmaceuticalcompositions, e.g. anti-inflammatory compositions, containing as anactive ingredient an effective amount, preferably between about 0.1 to45%, especially 1 to 25%, by weight based on the total weight of thecomposition, of one or more compounds according to the formula expressedabove and a non-toxic, pharmaceutically acceptable carrier or diluent.In addition, a pharmaceutical composition can comprise at least one ofthe subject compounds and a second component comprising at least oneother active compound. Such other active compounds include but are notlimited to, anti-inflammatory compounds for example, steroidalcompounds, including hydrocortisone and the like; or non-steroidalanti-inflammatories, including acetylsalicylic acid (aspirin),ibuprofen, acetaminophen, indomethacin, and the like. The second activeingredient can include antiviral, antibacterial, antifungal or otherantimicrobial compounds or antitumor compounds as well.

[0017] As described herein, the invention further comprises processesfor the production of compounds and compositions of the invention andnovel methods of use thereof, e.g. methods of inhibition of theinflammatory response in an animal.

[0018] In accordance with the invention, methods for inhibitinginflammation comprise administering to an animal in need of suchtreatment an effective amount of the pharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019]FIG. 1 shows the dose response for soritin A (HB-238) as measuredby percent inhibition of edema in the PMA-induced mouse earanti-inflammatory assay.

[0020]FIG. 2 shows the dose response for soritin A (HB-238) as measuredby percent inhibition of edema in the RTX-induced mouse earanti-inflammatory assay.

DETAILED DISCLOSURE OF THE INVENTION

[0021] The subject invention pertains to a novel use as ananti-inflammatory agent of bis-heterocyclic compounds and compositionscomprising the bis-heterocyclic compounds. Surprisingly, thebis-heterocycle compounds of the subject invention can be highlyeffective in inhibiting immunogenic and neurogenic inflammation.

[0022] In one example, compounds useful according to the subjectinvention have the following formula:

[0023] R₁₋₁₀ are the same or different selected from —H, —OH, halogen,—COOH, —COOR, C1-C8 alkyl , C1-C8 alkoxyl, mesyl, tosyl, —OCOR, or NZ₁Z₂(wherein the Zs can be the same or different);

[0024] X₁ and X₂ are the same or different selected from —H, —R, —COY,C(NZ₁)Y

[0025] Y is —H, —OH, NZ₁Z₂ (wherein the Z₁ and Z₂ can be the same ordifferent) C1-C8 alkyl, C1-C8 alkoxyl or an amino acid linked throughthe amine functionality forming an amide bond;

[0026] Z₁ and Z₂ are the same or different and independently selectedfrom —H, —OH, C1-C8 alkyl, C1-C8 alkoxyl or —COR;

[0027] R is C1-C8 alkyl, or aryl

[0028] A preferred embodiment of the subject invention pertains to thebis-indole compounds soritin A, HB-238, (I), Bis(3,3′indolyl)methane,HB-236, (II) and 2,2-Bis(3,3′indolyl) acetaldehyde, HB-237 (III).

[0029] Skilled chemists having the benefit of the instant disclosure canreadily use standard synthetic procedures to prepare the subjectcompounds. A variety of coupling procedures can be used includingdimerization of indoles with aldehydes, Friedel Craft acylations,Friedel Craft alkylations and various metal mediated coupling reactions.Preparation of amino acid substituted soritin A can easily be conductedusing standard peptide coupling reagents such as DCC, BOP, PyBOP, HBTUand TBTU.

[0030] A novel use for the described compounds and compositions is theiradministration to an animal, e.g., a human, as an agent in the controlof a neurogenic or immunogenic inflammatory response. The determinationthat the subject compounds have inhibitory activity against immunogenicand neurogenic inflammation is unexpected and advantageous.

[0031] Anti-inflammatory activity can occur by modes of action which caninclude, but are not limited to, lipid-mediated inflammatory responses,e.g. (i) suppression of cellular activation of phospholipase A2, eitherdirectly (as is known for the anti-inflammatory compound, manoalide) orindirectly (as is known for the anti-inflammatory compound,hydrocortisone); (ii) by inhibiting, or controlling, cyclooxygenation ofarachidonic acid, similar to the action of non-steroidalanti-inflammatory drugs; or (iii) by affecting lipooxygenase products ofperoxidase reactions to arachidonic acid, or by non-lipid-mediatedinflammatory responses, e.g., protease-induced inflammatory responses,and the like.

[0032] The compounds and compositions of the subject inventionadvantageously can block the immunogenic inflammatory pathway, therebyproviding a method for inhibiting immunogenic inflammation. Accordingly,the subject compounds and compositions can be useful in the treatment ofacute allergic response, asthma, rheumatoid arthritis, osteoarthritisand other inflammatory conditions involving acute and/or chronic jointinflammation.

[0033] Neurogenic inflammation is evoked by neuropeptides released fromprimary afferent nerve terminals and by other secondarily releasedinflammatory mediators. Specifically, neurogenic inflammation can beevoked by neuropeptides, such as substance P (SP), calcitoningene-related peptide (CGRP), vasoactive intestinal peptide (VIP), andneurokinin A (NKA), released from primary afferent C-fiber nerveterminals and histamine, secondarily released from mast cells (Dray, A.[1992] “Neuro pharmacological mechanisms of capsaicin and relatedsubstances” Biochem Pharm 44(4):611-15).

[0034] It is known that capsaicin (CAP), the active constituent found incayenne pepper, induces an acute neurogenic inflammatory response whenapplied topically to skin. CAP is a highly selective pain producingsubstance that selectively stimulates nociceptive and thermal-sensitivenerve endings in tissues by acting on a specific membrane receptor. Themode of action of capsaicin therefore differs significantly from phorbolmyristate acetate (PMA)-induced inflammation. By comparison, PMA elicitsits pro-inflammatory effects through cellular activation of specificimmune cells, such as macrophages and neutrophils. Consequently, thepain response to PMA develops more slowly than the immediate, buttransient, pain response to capsaicin.

[0035] The compounds and compositions of the subject inventionadvantageously can block the nociceptive (CAP-induced) inflammatorypathway, thereby providing a method for inhibiting neurogenicinflammation. Accordingly, the subject compounds and compositions can beuseful in the treatment of chronic pain, migraines, thermal-inducedpain, such as sunburn, or other thermal and nociceptive pain, andchronic pain associated with arthritis. Uses can also include otherinflammatory conditions that involve a neurogenic pain-producingcomponent, e.g., certain metastic carcinomas or inflammation of theblood vessels.

[0036] For purposes of the subject invention, unless otherwise noted,the terms “inflammation” and “inflammatory response” refer to any andall such inflammatory reactions including, but not limited to,immune-related responses and/or allergic reactions to a physical,chemical, or biological stimulus. “Anti-neurogenic inflammatoryactivity,” as used herein, will be understood by those of ordinary skillin the art to mean biological activity inhibiting or controlling aneurogenic inflammatory response.

[0037] The compounds of the subject invention can be used to treat avariety of skin conditions including, but not limited to, radiationirritation and burns (including UV and ionizing), chemical burns,rhinitis, thermal burns, and reddening of the skin.

[0038] The compounds of the subject invention can also be used topromote wound healing.

[0039] Following are examples which illustrate procedures for practicingthe invention. A more complete understanding of the invention can beobtained by reference to the following specific examples of compounds,compositions, and methods of the invention. It will be apparent to thoseskilled in the art that the examples involve use of materials andreagents that are commercially available from known sources, e.g.,chemical supply houses, so no details are given respecting them. Theseexamples should not be construed as limiting. All percentages are byweight and all solvent mixture proportions are by volume unlessotherwise noted.

EXAMPLE 1 Preparation of Soritin A, HB-238 (I)

[0040] One equivalent of indole was suspended in water and oneequivalent of glyoxylic acid was added. The mixture was vigorouslystirred at 85° C. for three hours during which a brown precipitate wasformed. The precipitate was filtered and dissolved in aqueous NaOHsolution (pH=12). Upon acidification (pH =2) with 5 N HCl, the productprecipitated and was filtered and dried in vacuum. Yield: 84.5%

[0041] Characterization: pink crystals, mp: 182 ° C. (decomposition) ¹HNMR (δDMSO-d₆): 12.60 (brs, 1H), 10.96 (2H, s), 7.78 (2H, d, J=8.3),7.54 (2H, d, J=8.3), 7.43 (2H, s), 7.22 (2H, t, J=7.4), 7.13 (t, 2H,J=7.4), 5.63 (1H,s).

[0042]¹³C NMR (δDMSO-d₆): 174.9, 136.7, 126.9, 124.0, 121.4, 119.3,118.8, 113.2, 111.8, 40.8.

EXAMPLE 2 Synthesis of Bis(3,3′indolyl)methane, HB-236 (II)

[0043] Two equivalents of indole was suspended in water and oneequivalent of formaldeyde (as formalin) was added. The mixture wasvigorously stirred at 85° C. in the dark. After approximately 30minutes, the product started to precipitate and the reaction mixture wasstirred for another five hours. The product was filtered andrecrystallized from methanol to yield white crystals. Yield: 79.3%

[0044] Characterization: white crystals, mp: 162° C. ¹H NMR (δDMSO-d₆):10.71 (2H, s), 7.53 (2H, d, J=8.0), 7.32 (2H, d, J=8.0),7.14(2H, s),7.04 (2H, t, J=7.2), 6.93 (t, 2H, J=7.2), 4.14 (2H, s). ¹³C. NMR(δDMSO-d₆): 136.4, 127.2, 122.7, 120.7, 118.6, 118.0, 114.2, 111.2, 20.9

EXAMPLE 3 Synthesis of 2,2-Bis(3,3′indolyl) acetaldehyde, HB-237 (III)

[0045] Two equivalents of indole was suspended in water and oneequivalent of acetaldehyde dimethyl acetal was added. The mixture wasvigorously stirred at 85° C. in the dark. The product started toprecipitate and the reaction mixture was stirred for another five hours.The product was filtered and recrystallized from methanol. Yield: 59%

[0046] Characterization: yellowish crystals, mp: 172° C. ¹H NMR(δDMSO-d₆): 10.72 (2H, s), 7.47 (2H, d, J=8.3), 7.34 (2H, d, J=8.3),7.15 (2H, s), 7.03 (2H, t, J=7.4), 6.89 (t, 2H, J=7.4), 4.61 (1H, q,J=7.4), 1.78 (3H. d. J=7.4). ¹³C NMR (δDMSO-d₆): 136.8, 126.7, 121.7,120.8, 120.3, 119.2, 118.0, 111.5, 28.0, 22.1.

EXAMPLE 4 Inhibition of PMA-Induced Inflammation (Edema) of the MouseEar

[0047] The test compound and a known inflammatory agent, phorbolmyristate acetate (PMA), are topically applied simultaneously to theleft ears of mice. Three hours and 20 minutes following application, themice are sacrificed. Both left ears and right ears are removed andstandard sized bores taken. Edema (inflammation) is measured as thedifference in weight between left and right ears (Van Arman, C. G.[1974] Clin. Pharmacol. Ther. 16:900-904.)

[0048] Bis-heterocycle compounds of the subject invention, e.g., thebis-indole compounds, show significant anti-inflammatory properties.When screened for the ability to reduce edema in mouse ears caused byapplication of phorbol myristate acetate, soritin A (I) was found tohave greater potency than the known anti-inflammatories hydrocortisone,indomethacin, manoalide and topsentin (See Tables 1 and 2). TABLE 1Relative potency of soritin A, (I), topsentin, manoalide, hydrocortisoneand indomethacin in the topical inhibition of PMA-induced mouse earedema Compound ED₅₀ (ug/ear) Hydrocortisone 20 Indomethacin 250Manoalide 100 Topsentin 15 Soritin A (I) 1.3

[0049] TABLE 2 Right Left Stan- % Inh. ear ear Difference dard OfTreatment (mg) (mg) (mg) Mean Dev. SEM Edema PMA 10 23.2 13.2 13.7 0.60.3 Control 9.5 22.8 13.32 2 μg/ear 8.6 23.2 14.6 10.1 23.6 13.5Compound I 10.3 12.0 1.7 1.7 0.4 0.2 87.5 dose: 50 10.2 11.8 1.6 μg/ear10.5 12.7 2.2 10.0 11.3 1.3 Compound I 9.9 11.6 1.7 2.1 1.3 0.7 84.9dose: 25 9.9 13.3 3.4 μg/ear 12.5 12.9 0.4 9.5 12.7 2.8 Compound I 9.513.6 4.1 3.1 1.9 0.9 77.3 dose: 12.5 8.8 10.7 1.9 μg/ear 9.8 11.0 1.29.7 14.9 5.2 Compound I 10.8 12.0 1.2 3.4 2.0 1.0 75.1 dose: 6.25 8.513.0 4.5 μg/ear 8.6 11.0 2.4 9.9 15.4 5.5 Compound I 10.2 14.2 4.0 6.42.6 1.3 52.9 dose: 3.12 9.0 17.7 8.7 μg/ear 9.2 17.9 8.7 8.6 12.9 4.3

EXAMPLE 5 Inhibition of Resiniferatoxin-Induced Inflammation (Edema) ofthe Mouse Ear

[0050] Induction of mouse ear edema can be conducted according to knownmethods (Inoue, 1-f., N. Nagata, Y. Koshffiara [1993]). Compounds to betested for anti-neurogenic inflammatory activity are topically appliedin acetone to the ears of mice in a solution that includes theedema-causing irritant resiniferatoxin (RTX). RTX alone (0.1 μg/ear) orin combination with various dilutions of test compound are applied toboth sides of the left ears (5 mice per treatment group) and acetone isapplied to all right ears. After a 30-minute incubation, the mice aresacrificed, the ears removed, and bores taken and weighed. Edema ismeasured by subtracting the weight of the right ear (acetone control)from the weight of the left ear (treated). Results are recorded as %decrease (inhibition) or % increase (potentiation) in edema relative tothe control group edema.

[0051] Soritin A proved to be capable of reducing edema in mouse earscaused by application of resiniferatoxin (RTX). At a dose of 50 μg/earof soritin A (I), RTX-induced edema was inhibited by approximately97.7%. The ED₅₀ for inhibition of RTX-induced edema was observed to be5.1 μg/ear (Table 3). TABLE 3 Right Left Stan- % Inh. ear ear Differencedard Of Treatment (mg) (mg) (mg) Mean Dev. SEM Edema RTX 10.2 20.2 10.012.0 2.2 1.0 Control 10.5 23.7 13.2 0.1 μg/ear 10.3 24.4 14.1 10.9 24.413.5 11.2 20.5 9.3 Compound I 9.9 14.0 4.1 1.5 1.7 0.7 87.9 25 μg/ear9.7 9.9 0.2 10.0 12.1 2.1 11.7 12.3 0.6 10.6 10.9 0.3 Compound I 12.115.9 3.8 2.8 1.1 0.5 76.8 12.5 μg/ear 10.6 14.2 3.6 10.7 13.8 3.1 10.711.8 1.1 10.9 12.6 1.7 11.1 14.5 3.4 Compound I 11.2 17.2 6.0 8.0 2.41.0 33.6 6.25 μg/ear 11.9 23.1 11.2 11.8 19.1 7.3 10.6 20.7 10.1 12.620.9 8.3 11.8 16.8 5.0 Compound I 12.2 18.2 6.0 6.0 1.0 0.4 49.9 3.12μg/ear 10.8 16.8 6.0 10.6 17.2 6.6 12.6 19.7 7.1 12.0 16.1 4.1 11.8 18.16.3

[0052] In addition, the bis-indole compounds Bis(3,3′indolyl)methane(II) and 2,2-Bis(3,3′indolyl) acetaldehyde (III) were tested for percentinhibition of RTX-induced edema. These compounds also show activity inthis assay (Table 4). TABLE 4 Percent inhibition of RTX-induced edema inmouse ears by soritin A and analogs Compound % Inhibition of Name Doseedema Soritin A HB-238 50 μg/ear 97.7 Bis(3,3′indolyl)methane HB-236 50μg/ear 59.1 Bis(3,3′indolyl)acetaldehyde HB-237 50 μg/ear 50.1

EXAMPLE 6 Formulation and Administration

[0053] The compounds of the invention are useful for variousnon-therapeutic and therapeutic purposes. It is apparent from thetesting that the compounds of the invention are effective foranti-inflammatory uses.

[0054] Therapeutic application of the new compounds and compositionscontaining them can be contemplated to be accomplished by any suitabletherapeutic method and technique presently or prospectively known tothose skilled in the art. Further the compounds of the invention haveuse as starting material for intermediates for the preparation of otheruseful compounds and compositions.

[0055] In one preferred embodiment, the compounds or compositions of thesubject invention are administered in a lotion or other cosmeticpreparation. This administration is done directly to the skin whereanti-inflammatory activity is desired.

[0056] The dosage administration to a host in the above indications willbe dependent upon the identity of the condition to be treated, the typeof host involved, its age, weight, health, kind of concurrent treatment,if any, frequency of treatment, and therapeutic ration.

[0057] The compounds of the subject invention can be formulatedaccording to known methods for preparing pharmaceutically usefulcompositions. Formulations are described in detail in a number ofsources which are well known and readily available to those skilled inthe art. For example, Remington's Pharmaceutical Science by E. W. Martindescribes formulations which can be used in connection with the subjectinvention. In general, the compositions of the subject invention will beformulated such that an effective amount of the bioactive compound(s) iscombined with a suitable carrier in order to facilitate effectiveadministration of the composition.

[0058] Typically, the compositions of the subject invention will beformulated and packaged in a manner particularly adapted for use as ananti-inflammatory agent. Thus, such compositions would typically beaccompanied with labeling or other literature describing the use of thecomposition as an anti-inflammatory agent.

[0059] In accordance with the invention, pharmaceutical compositionscomprising, as active ingredient, an effective amount of one or more ofthe subject compounds and one or more non-toxic, pharmaceuticallyacceptable carriers or diluents can be used by persons of ordinary skillin the art. In addition, the pharmaceutical composition can comprise oneor more of the bis-heterocycle compounds, e.g, a bis-indole, as a firstactive ingredient plus a second active ingredient comprising ananti-inflammatory compound known in the art. Such knownanti-inflammatory drugs include, but are not limited to, the steroidalanti-inflammatory drugs and the non-steroidal anti-inflammatory drugs(NSAIDs).

[0060] In accordance with this invention, pharmaceutically effectiveamounts of a known anti-inflammatory agent and the bis-heterocyclecompounds are administered sequentially or concurrently to the patient.The most effective mode of administration and dosage regimen ofbis-heterocycle compounds and anti-inflammatory agent will depend uponthe type of condition to be treated, the severity and course of thatcondition, previous therapy, the patient's health status, and responseto bis-indoles and the judgment of the treating physician.Bis-heterocycle compositions may be administered to the patient at onetime or over a series of treatments.

[0061] Preferably, the bis-heterocycle, e.g., a bis-indole composition,and any second anti-inflammatory agent are administered sequentially tothe patient, with the anti-inflammatory agent being administered before,after, or both before and after treatment with the bis-indole compound.Sequential administration involves treatment with the anti-inflammatoryagent at least on the same day (within 24 hours) of treatment withbis-indole and may involve continued treatment with theanti-inflammatory agent on days that the bis-indole is not administered.Conventional modes of administration and standard dosage regimens ofanti-inflammatory agents may be used (see Gilman, A. G. et. al. [eds]The Pharmacological Basis of Therapeutics, pp. 697-713, 1482, 1489-1491[1980]; Physicians Desk Reference, 1985 Edition). For example,indomethacin can be administered orally at a dosage of about 25-50 mg,three times a day. Higher doses can also be used. Alternatively, aspirin(about 1500-2000 mg/day), ibuprofen (about 1200-3200 mg/day), orconventional therapeutic doses of other anti-inflammatory agents can beused. Dosages of anti-inflammatory agents can be titrated to theindividual patient.

[0062] According to one embodiment of this invention, the patient mayreceive concurrent treatments with the anti-inflammatory agents andcompositions comprising bis-heterocycles, e.g. bis-indoles. For example,local intralesional, or intravenous injection of bis-indoles ispreferred (see Gilman et. al. supra at pp. 1290-91). Theanti-inflammatory agent should preferably be administered bysubcutaneous injection, subcutaneous slow release implant, or orally.

[0063] Alternatively, the patient can receive a composition comprising acombination of one or more bis-indole compounds and an anti-inflammatoryagent according to conventional modes of administration of agents whichexhibit antibacterial, anticancer, antitumor or anti-inflammatoryactivity. These include, for example, parenteral, subcutaneous,intravenous, or intralesional routes of administration.

[0064] The compounds used in these therapies can also be in a variety offorms. These include for example, solid, semi-solid and liquid dosageforms, such as tablets, pills, powders, liquid solutions or suspensions,suppositories, injectable and infusible solutions. The preferred formdepends on the intended mode of administration and therapeuticapplication. The compositions also preferably include conventionalpharmaceutically acceptable carriers and adjuvants which are known tothose of skill in the art. Preferably, the compositions of the inventionare in the form of a unit dose and will usually be administered to thepatient one or more times a day.

[0065] The compounds of the subject invention may also be administeredutilizing liposome technology, slow release capsules, implantable pumps,and biodegradable containers. These delivery methods can,advantageously, provide a uniform dosage over an extended period oftime.

[0066] Examples of such carriers or diluents include ethanol, dimethylsulfoxide, glycerol, silica, alumina, starch and equivalent carriers anddiluents. While effective amounts may vary, as conditions in whichcompositions are used vary, a minimal dosage required foranti-inflammatory activity is generally between 0.01 and 100 μg of thecompound. To provide for the administration of such dosages for thedesired therapeutic treatment, new pharmaceutical compositions of theinvention will advantageously comprise between about 0.1% and 45%, andespecially m, 1 and 15% by weight of the total of one or more of the newcompounds based on the weight of the total composition including carrieror diluent.

[0067] Illustratively, dosage levels of the administered activeingredients can be: intravenous, 0.01 to about 50 mg/kg;intraperitoneal, 0.01 to about 100 mg/kg; subcutaneous, 0.01 to about100 mg/kg; intramuscular, 0.01 to about 100 mg/kg; orally 0.01 to about200 mg/kg and preferably about 1 to 100 mg/kg; intranasal instillation,0.01 to about 50 mg/kg; and aerosol, 0.01 to about 50 mg/kg of animal(body) weight.

[0068] Once improvement of the patient's condition has occurred, amaintenance dose is administered if necessary. Subsequently, the dosageor the frequency of administration, or both, may be reduced as afunction of the symptoms to a level at which the improved condition isretained. When the symptoms have been alleviated to the desired level,treatment should cease. Patients may however require intermittenttreatment on a long-term basis upon any recurrence of disease symptoms.

[0069] It should be understood that the examples and embodimentsdescribed herein are of illustrative purposes only and that variousmodification or changes in light thereof will be suggested to personsskilled in the art and are to be included within the spirit and purviewof this application and the scope of the appended claims.

1. A method of treating inflammation in a human or animal, wherein saidmethod comprises administering to said human or animal an effectiveamount of a compound having the following structure:

wherein R₁₋₁₀ are the same or different and are selected from the groupconsisting of —H, —OH, halogen, —COOH, —COOR, C1-C8 alkyl, C1-C8alkoxyl, mesyl, tosyl, —OCOR, and NZ₁Z₂ (wherein the Zs can be the sameor different); X₁ and X₂ are the same or different and are selected fromthe group consisting of —H, —R, —COY, and C(NZ₁)Y; Y is —H, —OH, NZ₁Z₂(wherein the Z₁ and Z₂ can be the same or different) C1-C8 alkyl, C1-C8alkoxyl or an amino acid linked through the amine functionality formingan amide bond; Z₁ and Z₂ are the same or different and are selected fromthe group consisting of —H, —OH, C1-C8 alkyl, C1-C8 alkoxyl and —COR;and R is C1-C8 alkyl, or aryl.
 2. The method, according to claim 1 ,wherein X₁=H, X₂=COOH, R₁-R₁₀=H and Z₁, Z₂=H.
 3. The method, accordingto claim 1 , wherein X₁=X₂=H, R₁-R₁₀ are H, and Z₁=Z₂=H.
 4. The method,according to claim 1 , wherein X₁=H, X₂=CH₃, R₁-R₁₀ are H and Z₁=Z₂=H.5. The method, according to claim 1 , wherein said method is used totreat inflammation of immunogenic origin.
 6. The method, according toclaim 1 , wherein said method is used to treat inflammation in which theprimary activating inflammation is of neurogenic origin.
 7. The method,according to claim 6 , wherein said method is used to block anociceptive inflammatory pathway.
 8. The method, according to claim 1 ,wherein said compound is administered as a pharmaceutical composition,said pharmaceutical composition comprising one or more compounds ofclaim 1 and an acceptable pharmaceutical carrier.
 9. The method,according to claim 1 , wherein said compound is administered as acosmetic composition.
 10. A composition specifically adapted for use intreating inflammation wherein said composition comprises a compoundhaving the following structure:

wherein R₁₋₁₀ are the same or different and are selected from the groupconsisting of —H, —OH, halogen, —COOH, —COOR, C1-C8 alkyl, C1-C8alkoxyl, mesyl, tosyl, —OCOR, and NZ₁Z₂ (wherein the Zs can be the sameor different); X₁ and X₂ are the same or different and are selected fromthe group consisting of —H, —R, —COY, and C(NZ₁)Y; Y is —H, —OH, NZ₁Z₂(wherein the Z₁ and Z₂ can be the same or different) C1-C8 alkyl, C1-C8alkoxyl or an amino acid linked through the amine functionality formingan amide bond; Z₁ and Z₂ are the same or different and are selected fromthe group consisting of —H, —OH, C1-C8 alkyl, C1-C8 alkoxyl and —COR;and R is C1-C8 alkyl, or aryl.
 11. The composition, according to claim10 , wherein X₁=H, X₂=COOH, R₁-R₁₀=H and Z₁,Z₂=H.
 12. The composition,according to claim 10 , wherein X₁=X₂=H, R₁-R₁₀ are H and Z₁=Z₂=H. 13.The composition, according to claim 10 , wherein X₁=H, X₂=CH₃, R₁-R₁₀are H and Z₁=Z₂=H.
 14. The composition, according to claim 10 , whereinsaid composition further comprises a second active ingredient.
 15. Thecomposition, according to claim 14 , wherein said second active agent isselected from the group consisting of a steroidal anti-inflammatorycompound, a non-steroidal anti-inflammatory compound, an antiviralcompound, an antibacterial compound, an antifungal compound, and ananti-tumor compound.
 16. The composition, according to claim 10 ,wherein said compound is about 0.1% to about 45% weight percent of saidcomposition.
 17. The composition, according to claim 16 , wherein saidcompound is about 1% to about 25%, weight percent, of said composition.18. A method for treating a condition, in a human or animal, whereinsaid condition is selected from the group consisting of pain; burns;allergic responses; rheumatoid arthritis; osteoarthritis; otherinflammatory conditions involving acute joint inflammation, chronicjoint inflammation, or both; wound healing; anaphylactic reactions;inflammatory bowel disease; nephritis; conjunctivitis; inflammatory gumdisease; acute asthmatic attack and inflammation of the lung due tochemical exposure, said method comprising administering an effectiveamount of a bis-heterocyclic compound or a salt, analog, or derivativethereof, wherein said compound has the following structure:

wherein R₁-R₁₀ are the same or different and are selected from the groupconsisting of —H, —OH, halogen, —COOH, —COOR, C1-C8 alkyl, C1-C8alkoxyl, mesyl, tosyl, —OCOR, and NZ₁Z₂ (wherein the Zs can be the sameor different); X₁ and X₂ are the same or different and are selected fromthe group consisting of —H, —R, —COY, and C(NZ₁)Y; Y is —H, —OH, NZ₁Z₂(wherein the Z₁ and Z₂ can be the same or different) C1-C8 alkyl, C1-C8alkoxyl or an amino acid linked through the amine functionality formingan amide bond; Z₁ and Z₂ are the same or different and are selected fromthe group consisting of —H, —OH, C1-C8 alkyl, C1-C8 alkoxyl and —COR;and R is C1-C8 alkyl, or aryl.
 19. The method, according to claim 18 ,wherein said pain is caused by a condition selected from the groupconsisting of migraine, rhinitis, thermal induced pain, radiationinduced pain, and chemical induced pain.
 20. The method, according toclaim 18 , wherein said bum is selected from the group consisting ofchemical burns, chemical induced lesions, radiation burns, and thermalburns.
 21. The method, according to claim 18 , wherein said condition isallergic response.
 22. The method, according to claim 18 , wherein saidtreatment facilitates the promotion of wound healing.
 23. The method,according to claim 18 , wherein said condition is a systemicanaphylactic reaction in an animal or a human.
 24. The method, accordingto claim 18 , wherein said condition is inflammatory bowel disease. 25.The method, according to claim 18 , wherein said condition is nephritis.26. The method, according to claim 18 , wherein said condition isconjunctivitis.
 27. The method, according to claim 18 , wherein saidcondition is inflammatory gum disease.
 28. The method, according toclaim 18 , wherein said condition is selected from the group consistingof acute asthmatic attack and inflammation of the lung from chemicalexposure.
 29. The method, according to claim 18 , wherein said conditionis selected from the group consisting of rheumatoid arthritis,osteoarthritis, and other inflammatory conditions involving acute jointinflammation, chronic joint inflammation, or both.